There are 600,000 patients in United States treated for end-stage renal diseases (ESRD) with 400,000 on dialysis. While the best treatment for ESRD is kidney transplantation over 100,000 patients are on the constantly growing waiting list because of the organ shortage. Although the annual number of kidney transplants from deceased donors remains rather unchanged (11,000) over the last decade, new research in organ donation suggests that the number of annual live kidney transplants (5,600) could increase by up to 50%. In particular, each year 3,000 patients with a willing live donor are not transplanted because of blood incompatibility (50%) or previously acquired sensitization against their donor (50%). To accommodate these patients, kidney paired donation (KPD) programs find matches among these incompatible pairs and arrange exchanges of donors. However, due to the difficulty in finding matching donors for sensitized patients who are 50% of patients in KPD programs, there is a need for a significant improvement in searching methods. The evaluation for sensitized patients is outdated and incomplete, as it is recommended to identify histocompatibility leukocyte antigen (HLA)-A, -B, -DR, -DQ antigens at low (2-digit) resolution (in KPD UNOS pilot: HLA-A,-B,-Bw4,6, -Cw,-DR,-DQ and -DP with -DR51/52/53 antigens at the level of split resolution.). This requirement does not correspond to the patient's antibody (Ab) reactivity measured at allele (4-digit) level by a single antigen bead (SAB) assay. In addition, the permission to perform transplant is based on the negative flow crossmatch (FXM) with donor cells which often does not correlate with the virtual crossmatch (VXM). In fact, our recent data suggest that negative FXM may fail to discover dangerous donor-specific Abs (DSA) in highly sensitized patients. To overcome these problems 3 goals are proposed: 1) to use the most advanced Illumina Ion Torrent Next Generation Sequencing (NGS) method to identify 4-digit HLA-A, -B, -C, -DR, -DQ and -DP alleles for all KPD donors and recipients; 2) to improve donor-recipient matching algorithm using epitope based analysis of recipient antibodies to describe unacceptable alleles and acceptable mismatched alleles; and 3) to stratify the risk for sensitized patients by characterizing the strength of the epitope-defined DSA through dilution studies, typing of IgG subclasses relevant for complement (C')-binding activity (IgG3>IgG1>IgG2>IgG4), and C1q-binding assays for cytotoxic potentials. Patients deemed to be at high risk may then be considered for aggressive therapy and desensitization. Patient and donor 4-digit HLA typing and epitope analysis is expected to allow for the most effective selection of donors for sensitized patients both in KPD programs and through non-paired donation.